Major advances in the development of B cell hybridomas secreting monoclonal human antibodies were realized. Following in vivo immunization of normal humans with various preselected antigens such as KLH, tetanus toxoid, and pneumococcal polysaccharide, peripheral blood B cells were fused with a HAT sensitive mouse myeloma line to yield extremely stable (greater than 18 months) heterohybrids secreting large amounts (10-30 ug/ml) of monoclonal human antibody. Precise conditions for optimizing the yield of hybrids from human peripheral blood were delineated. T-T cell hybrids secreting immunoregulatory factors were established by the fusion of human blood T cells and a HAT sensitive human T cell leukemia line. Of note was the development of hybrids which secrete B cell growth factors devoid of T cell growth factor or B cell differentiation factor activity thus providing a source of purified factor for the continuous growth of B cell lines. Improved methodologies for the cloning of antigen-specific human T cells from peripheral blood were developed and resulted in the production of individual clones specific for KLH, tetanus toxoid or diphtheria toxoid. Both functional helper and suppressor clones were developed. These clones were antigen-specific and MHC restricted in the recognition of soluble antigen in the context of DR or MB antigen bearing presenting cells.